This application outlines research and career development plans for Jin Kyung Kim, whose long-term objective is to become an independent physician-scientist in cardiovascular research. She is a graduate of an NIH-funded M.D.-Ph.D. Program and has received rigorous training in internal medicine and cardiology. She is currently conducting research as part of her subspecialty fellowship under the auspice of the American Board of Internal Medicine Research Pathway. Her immediate goal includes successful completion of the ongoing research project and preparing for a career in academic cardiology and research. Her mentor, Dr. Ellis R. Levin, is Vice Chair of Medicine at the University of California, Irvine, and an established medical scientist in the field of cardiovascular research. An advisory committee of senior faculty members will provide additional guidance on the applicant's career and scientific progress. Dr. Kim has full institutional support for her proposed career development and research plan. The overall goal of the research proposal is to study the protective role of estrogen in cardiomyocytes. Initial work by the applicant revealed that estrogen-mediated survival of cardiomyocytes exposed to simulated ischemia-reperfusion.(l/R) depends on regulation of p38 alpha and p38 beta. The two kinase isoforms possess opposing functions in the cell fate (p38 alpha being pro-apoptotic and p38 beta pro-survival), but little is known about how the two modulate the apoptotic signaling. An attractive downstream target of the kinase is p53, a well-known mediator of apoptosis. The proposed experiments will test the hypothesis that the cytoprotective actions of estrogen involve regulation of p53 via p38. The specific aims are: (1) to study the effect of ligand-activated estrogen receptors on p53 in cardiomyocyte apoptosis, (2) to characterize the relationship between p38 alpha, p38 beta, and p53, (3) to examine how estrogen signaling to p53 via p38 impact the intrinsic mitochondrial death pathway. In addition to cultured rat cardiomyocytes for the in-vitro analysis of apoptosis and the relevant proteins, coronary artery ligation/release in ovariectomized mice with or without estrogen supplement will serve as an in-vivo model of I/R to correlate the in-vitro data. Findings from this research will further our understanding of how estrogen protects stressed heart muscle cells, and promote potential preventive and therapeutic options in ischemic heart disease. (End of Abstract)